The objective of this proposal is to understand the mechanism and define the potential of polymeric controlled oral gene delivery, using chitosan as a non-viral gene carrier. The Specific aims are (1) Design chitosan-DNA nanoparticles with different characteristics for oral delivery; (2) Characterize the cellular transport behavior of chitosan-DNA nanoparticles in-vitro; and (3) Characterize the gene transfer performance of chitosan-DNA nanoparticles in a rat model. Specific aim (1) will be achieved by assessing the effect of chitosan degree of deactylation on transfection efficiency and by formulating gelatin mini-capsules with delayed release characteristics. Specific aim (2) will be executed by identifying the important parameters affecting the transport of chitosan-DNA nanoparticles in a Caco-2-1ymphocyte co-culture model and determining the intracellular trafficking characteristics in Caco-2 cell culture using the quantum dot technology.